Basic ketones and salts thereof



alkyl portion thereof by the basic radical of a nitro, halogen and loweralkoxy. Free bases of the invention can be represented by the 1 formulaM. P. 175-176 C.

1 oxalic acid, citric acid and the like.

' fungal and antiprotozoal substances (active for phenyl styryl ketoneor of a hydroxyphenyl substituted by the basic radical of a secondaryPatented Feb. .9, 1954 UNITED STATES PATENT OFFICE BASIC KETONES ANDSALTS THEREOF Moses Wolf Goldberg, Upper Montclair, and Albert IsraelRachlin, Hackensack, N. J assignors to Hoffmann-La Roche Inc., Nutley,N. .L, a corporation of New Jersey No Drawing. Application July 21,1952, Serial No. 300,120

10 Claims. (01. 260-240) 1 2 This invention relates to novel chemicalcomdroxide in 100 cc. of water (30) was added 13.6 g. pounds, and moreparticularly, it relates to basic (0.1 m.) of p-hydroxyacetophenone and50 cc. ketones and their acid addition salts wherein of ethanol.2,4-dichlorobenzaldehyde (17.5 g., one valence of the keto group isattached to a 0.1 m.) was added and the solution was stirred loweralkoxyphenyl radical substituted in the 5 at room temperature for 20hours. The solution was poured into 2 liters of water and, withstirring, the mixture was acidified to Congo 'red keto group is attachedto a styryl radical or to a with hydrochloric acid. The product wasfilstyryl radical carrying at least one nuclear subtered, washed with500 cc. of water and then it stituent selected from the class consistingof was partially dried. The slightly damp product was recrystallizedfrom 1500 cc. of methanol to yield 4-hydroxyphenyl 2,4-dichlorostyrylketone.

secondary amine and the other valence of the (I) H B. To a stirredsolution of 20 g. of sodium hy- R I droxide in 200 cc. of water (30) wasadded ofl=o (nj* 27.2 g. (0.2 m.) of p-hydroxyacetophenone and 0 O1ower1ky1ene- 75 cc. of ethanol. o-Chlorobenzaldehyde (28.1 g.,

0.2 m.) was added and the solution was stirred w R d R e represents y eat room temperature for twenty hours. The

nitlo halogen g. chloro or bromo) or solution was poured into 2 litersof water and the lower alkoXy (e. g. met O Y y and mixture was acidifiedwith carbon dioxide. The B represents the radical of a secondary amineproduct was filtered, washed with 500 cc. of attached by the nitrogenatom to the lower water, and then it was air dried. Recrystallizedalkylene group, a dialkylflmino radical Such from 200 cc. of ethanol,the product, p-hydroxyas dimethylam a heterocyclic o a y phenylZ-chlorostyryl ketone, melted at 170 C. a i radi a such as 12,3, -t traydr qu n 1yl, c. To a stirred solution of 20 g. of sodium piperidyl ormorpholinyl. hydroxide in 200 cc. of water was added The invention alsoembraces acid addition 27.2 g. (0.2 m.) of p-hydroxyacetophenone and.salts of the above mentioned novel bases with 75 cc, of ethanol.p-chlorobenzaldehyde (28.1 g., d a m n ral acids and organic a ds, su n0.2 m.) was added and the solution was stirred as hydrochloric acid,sulfuric acid, acetic acid, 00 ,1; room temperature for twenty hours.The solution was poured into 2 liters of water and, with stirring, themixture was acidified to Congo red with hydrochloric acid. The productwas filtered, washed with 500 cc. of water, and then The compounds ofthe invention are antiinstance against Trz'chophyton mentagrophytes,

p0 limosum and T OmO aS v g it was air dried. Recrystallized from 350cc. of 'nalis), and are useful as pharmaceuticals.

ethanol, the product, p-hydroxyphenyl p-chloro- In general, the newcompounds can be made 'styryl ketone, melted at 188-490.

by reacting an alkali metal salt of a hydroxy- D. To a stirred solutionof 20 g. of sodium hydroxide in 200 cc. of water (30) was added 27.2 g.

(0.2 m.) of p-hydroxyacetophenone and 75 cc.

of ethanol. m-Nitrobenzaldehyde (30.2 g., 0.2

m.) was added and the slurry was stirred at room 'stituted-styryl ketonewith a haloalkane sub- 40 amine, as illustrated by the general equation1} R 0 OM wherein M represents an alkali metal, X represents a halogen,and R, R and R and B have temperature for twenty hours. The slurry waspoured into 4 liters of water and, with stirring, the same meaningsassigned to them above. the mixture was acidified to Congro red withCertain of the intermediates used in practicing hydrochloric acid. Theproduct was filtered, the invention are novel with us, and for comwashedwith 1 liter of water, and then it was air pleteness of disclosure, thepreparation thereof dried to yield p-hydroxyphenol m-nitrostyryl isdescribed below. 7

lszetone, M. P. 228-230 C. l 1 A. To a stirred solution of 10 g. ofsodium hy E. A mixture of 200 cc. of 10 percent sodium hydroxidesolution, 27.2 g. (0.2 m.) of m-hydroxyacetophenone, 28.8 g. (0.2 m.) of2,4-dichlorobenzaldehyde and 200 cc. of ethanol was stirred and refluxedfor twenty hours. The solution was poured into 3 liters of water and,with stirring, the mixture was acidified to pH 6 with hydro.- chloricacid. The product, which solidified on standing, was filtered, washedwith 500 cc. of

water, and then it was air dried. Recrystallized" from a mixture of 400cc. of glacialv acetic acid and 1'75 cc. of water, the product,m-hydrpxyphenyl 2,4-dich1orostyryl ketone, melted: at"1-21-- 124 C.

F. A mixture of 200 cc. oi 10. percent sodium i J):

hydroxide solution, 27.2 g. (0.2 m.) of m-hy droxyacetophenone, 28.1 g.(0.2 m.) of. O.-Qh1QIOr-- benzaldehyde and 200 cc. of ethanol wasstirred and refluxed for twenty hours. The solution was poured into 3liters of water and-withstir-- ring, the mixture was acidified to pH 6with carbontdioxide. The product; which. solidified; on standing-,; was:filtered, washed with; 500 cc. of water, and'then it. was. air dried.Recrystallized from; amixtureofi, 360' cc. of'glacialacetic acid and 150cc; of: water, the product, mehydroxyphienyl 2-chlorostyryll. ketone,melted: at 115- 1117 C;

The invention is; further. disclosed. in the following examples; whichare. illustrative but; not 1imitative-.thereo;. All: melting points arecorrected...

Ewample l Sodium; methoxide; (.31 g., 0.69m wasyadded to -a. solutionof". 14 ?1 g. (0.656 m.) of p hydroxyphenyl styrylketone [Kostanecki eta1'., Ber, 32, 1392414189911 in, 2.: liters. of. chlorobenzene containedin a :1iter stirred flask equippedwith a downward condenser.Chlorobenzene wasdistilled-cit. at.atmospheriapressure until. 800 cc. ofdistillate 'had beencollected. The. slurry. of the sodium salt wasstirred; while-it was. allowed to cool to room temperature.

Meanwhile free. pediethylaminoethyl chloride was liberated from the.hydrochloride as follows: 225: g.. (L31 m.) of crudefl-diethylaminoethyl chloride hydrochloride was suspended in 400 Co. atice-coldchlorobenzene. Two-hundred cc. of 50 percentsodiumhydroxidesolution: was added in portions withstirrin-g the entiremiXture-being rkept cold in an icebath. The-top layer was decanted. through a: sinteredglass. funnel. The bottom aqueous layer was: extracted three timeswith..200cc. portions of chlorobenzene. Allthe chlorobenzene' extractswere combined; and dried over magnesium sulfate in a refrigerator.

The; chlorobenzenesolution of the' e-diethylaminoethyl chlorideiwasfiltered from the; magnesium. sulfate, the filtrate; wasaddedto theslurry of. the. sodium salt of. p hydroxyphenyh styryl ketond-and. themixture was stirred and refluxed for four hours. The OhIOI'ObGRZE -Iewas removedby steam distillation and the. residue was allowed to cool toroom temperature. The oily base was extracted into two &00 cc. portionsof ether, the combined ether extracts were dried over magnesium sulfate,and the solvent was removed in vacuo. The crude base was dissolved in400- cc. of ethanol, a'solution of 83 g. (0.665 m.) of oxalicaciddihydrate in 250 cc. of warm ethanol was added, and the resultingsolution was allowed to cool to C. Ether (600 cc.) was added, theslightly turbid solution was seeded, and themixture" was allowed tostand in a cool place to crystallize. The product, p-(B-diethylamino- 4ethoxy pheny1 styryl ketone oxalate, had a melting point of 152-153 C.

Four grams of the oxalate were partitioned between 120 cc. of ether, 150cc. of water and 10 cc. of percent sodium hydroxide solution. The. etherlayer was dried over magnesium sulfate" and, after removal of thesolvent. the residue was dissolved in 3 cc. of ethanol andthis solutionwas treated with 3 cc. of 20 percent alcoholic. hydrogen bromide. Oncooling, the soluti'onset to a mass of white crystals. The product,pefifi-diethylaminoethoxy)phenyl styryl ketone: hydrobromide,recrystallized from 75 cc. of ethanol", melted at 170-172 C.

Example 2 Sndium hydroxide solution (4 00., 50 percent concentration)was added to a solution of 12.? g.

(0&5 m.) of p-hydroxyphenyl p-"nethoxystyryl ketone (Hiemeseh et al.,Chem. Zentralblatt 11925; 1,. 12.0.1.) in.v 39.0. cc. of;chlorobenzene-contained. in a 500 cc. stirred flaskequippedv with adownward; condense Themixturewas distilled at. atmospheric pressureuntil-200cc. of distillate had been collected. The slurry of the sodiumsalt. was stirred while it was allowed to coolfco room. temperature.

A chlorobenzene solution of B-diethylaminoethyl chloride (liberated in.the manner described in Example-1 from l7.2 g., 0 .1'm. ofcrudehydrochloride); was added tothe slur-ryof the; sodium salt of:pz-hydroxypheny'l p-methoxystyryl, ketone and the mixture was stirredand refiuxed-for four hours. The chlorobenzene was, removed by steamdistillation and the residue was allowed t cool to room temperature. Theoily base wasextracted; intothree 200cc. portions of ether, the combinedether extracts were dried over magnesiumv sulfate, and the. solvent wasremoved in vacuo The crude base wasdissolved in cc.

. uct', p (B diethylaminoethoxy)phenyl' p-methoxystyryl'ketonehydrobromide, melted at 134- 136 C.

Example 3 Sodium. hydroxide. solut o (.4. cc, 50 per ent conc ntration)W sa ded tea oiutiqn f 1.5.31- (0.054 m.) o--4-hydroxypheny12,,4-dichlorostyryl k tone in 300cc- 01f chloro n-zene ined in a 500 cstirred flask. u ppedwith a downwar condense T e mixtur was d s i l d tt spherio. pressure until 2% cc, of distillate had been collected-V Theslurry of. e. sod ume lt was stirred. hile it was lewed. to 000toroomtemperature- A. chlqro enzenes lution of fid ylaminothyl chl ride(liberated in. the mann r dese ibed in. Exampl 1 f m. 21s.. 0- f ru ehdrcchloride), was addedto the slurry of the sodium salt ofe-hydroxyphenyl 2,4-dichlorostyryl ketone and the mixturewas stirred andrefluxed for four hours. The chlorobenrpene was removed by steamdistillation and the residue was allowed to cool to room temperature.The oily base was extracted into three 200v cc. portions of ether, thecombined ether extracts were dried over magnesium sulfate, and thesolvent was removed. in vacuo. The-crude base was dissolved'in 25 cc; ofethanol, 50 cc. of 2'7 percent ethanolic-hydrogen bromide was added and,after standing for several hours in a cool place, a mass of lightyellow-crystals separated. Recrystallized from 200 cc. of ethanol, theproduct, p (,3 diethylaminoethoxy)phenyl 2,4-dichlorostyryl ketonehydrobromide, melted at 191-194" C.

Example 4 Sodium methoxide (8.2 g., 0.152 m.) was added to a solution of43 g. (0.147 m.) of l-hydroxyphenyl 2,4-dichlorostyryl ketone in 600 cc.of chlorobenzene contained in a 2 liter stirred flask equipped with adownward condenser. Chlorobenzene was distilled at atmospheric pressureuntil 300 cc. of distillate had been collected. The slurry of the sodiumsalt was stirred while it was allowed to cool to room temperature.

A chlorobenzene solution of fi-diethylaminoethyl chloride (liberated inthe manner described in Example 1 from 48 g., 0.28 m. of crudehydrochloride) was added to the slurry of the sodium salt of4-hydroxyphenyl 2,4-dichlorostyryl ketone and the mixture was stirredand refluxed for four hours. The chlorobenzene was removed by steamdistillation and the residue was allowed to cool to room temperature.The oily base was extracted into two 300 cc. portions of ether, thecombined ether extracts were dried over masnesium sulfate, and thesolvent was removed in vacuo. The crude base was dissolved in 100 cc. ofethanol, a solution of 21 g. (0.164 m.) of oxalic acid dihydrate in 75cc. of hot ethanol was added, and the resulting solution was allowed tocool to 30. Ether (250 cc.) Was added and the slightly turbid solution,on scratching, deposited a mass of crystals. Recrystallized from 400 cc.of

ethanol, the product, p-(p-diethylaminoethoxy) phenyl 2,4-dichlorostyrylketone oxalate, melted at 9193 C.

When the material was spread out in a thin layer and was allowed to airdry for several days,

it melted at 126-129 C.

Example 5 ethyl chloride (liberated in the manner described in Example 1from 34.4 g., 0.2 m. of crude hydrochloride) was added to the slurry ofthe sodium salt of p-hydroxyphenyl o-chlorostyryl ketone and the mixturewas stirred and refluxed for four hours. The chlorobenzene was removedby steam distillation and the residue was allowed to cool to roomtemperature. The oily base was extracted with three 200 cc. portions ofether, the combined ether extracts were dried over magnesium sulfate,and the solvent was removed in vacuo. The crude base was dissolved in 50cc. of ethanol, 50 cc. of 2'7 percent ethanolic hydrogen bromide wasadded and, after standing several hours in a cool place, a mass ofcrystals separated. Recrystallized from a mixture of 700 cc. of ethanoland 25 cc. of water, the product, p- (p-diethylaminoethoxy) phenyl2-chlorostyryl ketone hydrobromide, melted at 19'l-199 C.

Example 6 Sodium hydroxide solution ('7 cc., 50 percent concentration)was added to a solution of 21.5 g. (0.08 m.) of p-hydroxyphenyl3-nitrostyryl ketone in 300 cc. of chlorobenzene contained in a 500 cc.stirred flask equipped with a downward condenser. The mixture wasdistilled at atmospheric pressure until 200 cc. of distillate had beencollected. The slurry of the sodium salt was stirred while it wasallowed to cool to room temperature. l

. A chlorobenzene solution of p-diethylaminoethyl chloride (liberated inthe manner described in Example 1 from 43.5 g., 0.16 m. of crudehydrochloride) was added to the slurry of the sodium salt ofp-hydroxyphenyl 3-nitrostyryl ketone and the mixture was stirred andrefluxed for 4 hours. The chlorobenzene was removed by steamdistillation and the residue was allowed to cool to room temperature.The crystalline base was filtered, washed with water and dried. Thecrude base was dissolved in 100 cc. of ethanol, 25 cc. of 2'? percentethanolic hydrogen bromide was added and, after standing several hoursina cool place, a mass of crystals of p-(p-diethylaminoethoxy)phenyl-IS-nitrostyryl ketone hydrobromide, M. P. 202-204" C.separated.

Example 7 Sodium hydroxide solution (6 cc., 50 percent concentration)was added to a solution of 25.85 g. (0.1 m.) of p-hydroxyphenylp-chlorostyryl ketone in 300 cc. of chlorobenzene contained in a 500 cc.stirred flask equipped with a downward condenser. The mixture wasdistilled at atmospheric pressure until 200 cc. of distillate had beencollected. The slurry of the sodium salt was stirred while it wasallowed to cool to room temperature.

A chlorobenzene solution of fi-diethylaminoethyl chloride (liberated inthe manner described in Example 1 from 34.4 g., 0.2 m. of crudehydrochloride) was added to the slurry of the sodium salt ofp-hydroxyphenyl p-chlorostyryl ketone and the mixture was stirred andrefluxed for four hours. The chlorobenzene was removed by steamdistillation and the residue was allowed to cool to room temperature.The crystalline base was filtered, washed with water and'dried. Thecrude base was dissolved in cc. of ethanol, 35 cc. of 2'7 percentethanolic hydrogen bromide was added, and after standing several hoursin a cool place, a mass of p-(fi-diethylaminoethoxy)phenylp-chlorostyryl ketone hydrobromide crystals, M. P. 165-166" C.,separated.

Example 8 To a solution of 29.3 g. (0.1 m.) of m-hydroxyphenyl2,4-dichlorostyryl ketone in, 200 cc. of ethanol was added 6 g. (0.11m.) of sodium meth oxide. A chlorobenzene solution ofp-diethylaminoethyl chloride (liberated in the manner described inExample 1 from 24.4 g., 0.2m. of crude hydrochloride) was added to thesolution of the sodium salt of m-hydroxyphenyl 2,4-dichlorostyryl ketoneand the mixture was stirred and refluxed for four hours. The mixture wascooled, treated with 500 cc. of ether to complete the precipitation ofthe sodium chloride, filtered, and the filtrate was evaporated in vacuo.The residue was dissolved in cc. of ethanol, a solution of 15 g. ofoxalic acid dihydrate in 80 cc. of ethanol was added and, after 350;,cc.of ether had been added, the turbid solution was allowed to stand in acool place to crystallize. The crude evaporated in vacuo.

product wasrecrystallized ironic-a mixture of cc; ofiethanol-and '20 cc.of water to: give 111- (13- :diethylaminoethoxy)phenyl2,4-dichlorostyryl iketone oxalate, M. P. 148-151 0.

Example 9 'To'a' solution of 18.1 g. (0.07 ni.) of m-hydroxyphenyl2-chlorostyryl ketone in 200 cc. of ethanol was added 4.7 g. (0.07 m.)of sodium methoxide.

lA chlorobenzene solution of e' diethylaminoethyl 'chloride (liberatedin the manner described in "Example 1 from 24 g., 0.14 m. of crudehydrochloride) was added to the solution of the sodium salt ofm-hydroxyphenyl 2-chlorostyryl ketone and the mixture was stirred andrefluxed for four hours. The mixture was cooled, treated with 500crystallized from 350 cc. of isopropanol to give m-(e-diethylaminoethoxy) phenyl 2-chlorostyryl ketone oxalate, M. P.121-124= C.

Example To a solution of 11.2 g. (0.05 m.) of Z-hydroxyf phen'yl styrylketone [Feuerstein et al., Ber. 31, 715 (1898)] in 250 cc. of ethanolwas added 3 g. (0.055 m.) of sodium methoxide. 'z'ene solution ofe-diethylaminoethyl chloride (liberated in the manner described inExample 1 from 17.2 g., 0.1 m. of crude hydrochloride) was Achlorobenadded to the solution of the sodium salt of 2- hydroxyphenylstyryl ketone and'the mixture was stirred and refluxed for four hours.The mixture 'was cooled, treated with 500 cc. of ether to complete theprecipitation of sodium chloride, filtered, and the filtrate wasevaporated in vacuo.

' The residue was dissolved in 100 cc. of ethanol, a solution of 6.3 g.of oxalic acid dihydrate was added and the solution was allowed to standin a cool place to crystallize.

The crude product was recrystallized from a mixture of 250 cc. of

benzene and cc. of ethanol to give o-(B-di- 'ethylaminoethoxy)phenylstyryl ketone oxalate,

Example 11 A mixture of"33.6 g (0.15 m.) of p-hydroxyphenyl styrylketone (see Example 1), 350 cc. of

chlorobenzene and 8.4 g. (0.155 m.) of sodium 1 methoxide was stirredand heated to the boiling point. i of p-hydroxyphenyl styryl ketone wasallowed to cool to 10, 26.5 g. (0.177 m.) y-morpholinylpropyl: chloridewas added and the mixture was stirred and refluxed for eighteen hours.

The resulting slurry of the sodium salt After removing the sodiumchloride by filtration, the

, mother liquor was evaporated in vacuo. The res- 3 idue, crude p- ['y-(e-morpholyl) propoxy] phenyl styryl ketone, set to a mass of crystals.Recrystallized from 350 cc. of ethanol, the product had a melting pointof 89-91" C.

A solution of 41.5 g. (0.118 m.) of the base (melting point 89-91" 0.,obtained above) in 300 cc of warm ethanol was added to a solution of25g. (0.12am) of citric acid monohydrate in 100 f'c'efof ethanoljpoxylphenyl' styryl ketone citrate, which separated on cooling, wasrecrystallized from a'mix- The ply-( hmorpholinyl) proture, of 700- cc.or ethanol and 10006.. of water. M. P. 151-153 C. withdecomposition.

Example 12 Example 13 The free base p ('y diethylaminopropoxy) phenylstyryl ketone was prepared by a procedure similar to that described inExample 11. From 33.6 g; (0.15 m.) of p-hydroxyphenyl styryl ketone (seeExample 1) and 24.6 g. (0.132 m.) of 3-chloroprop-yl-N-diethylaminethere was obtained 17 g. of the oily base. The base was converted to p('y diethylaminopropoxy)phenyl styryl ketone citrate in the mannerdescribed in Example 11, by treatment with citric acid monohydrate. M.P. of the citrate, 142-143 C. with decomposition.

Example 14 The free base p-(fi-dimethylaminoethoxy)- p yl yryl k ne wasprepared by a procedure similar to that described in Example 11. From g.(0.15 m.) of p-hydroxyphenyl styryl ketone (see Example 1) and,c-dimethylaminoethyl'chloride (liberated from d3 g., 0.3 m. of thehydrochloride) there was obtained 41 g. of crude crystalline base, M. P.67.5-'l0 C. The base was con- 'verted to the citrate in the mannerdescribed in Example 11. M. P. 132-134. C.

W e claim:

1. A compound selected from the group consisting of bases having thefollowing formula and-their acid addition salts; wherein R, R and R eachrepresents a'member of the group consisting of hydrogen, lower alkoxy,halogen and nitro, n representsan integer from 2 to 3 inch).-

C(CHzh- 'sive. and B represents a'radical of the group consisting ofdi(lower alkyl) amino, 4-morpholinyl and I-piperidyl.

2. A basic ketone having one Valence of the keto group attached to alower alkoxyph'enyl radical having from two to three carbon atoms in thealkyl portion thereof and substituted in the alkyl portion thereof by adi(lower alkyDamino radical, and having the other valence of the ketogroup attached to the styryl radical.

3. An acid addition salt of a compound according to claim 2.

4. A basic ketone having one valence of the ket'o group attached to alower alkoxyphenylradicalhaving from two to three carbon atoms in theallzyl portion thereof and substituted in the alkyl portion thereof. by..a. di(lower alkyhamino radical, and having the other valence of theketo group attached to the:2,4-dichlorostyryl radical.

5. An acid additibn salt of a compound accord- 10. p (l-piperidyl)propoxyjl henyl styryl ing to claim 4. ketone citrate.

6. p-Di- (lower alkyl) aminoethoxyphenyl styryl MOSES WOLF GOLDBERG.ketone. ALBERT ISRAEL RACHLIN.

7. An acid addition salt of a compound accord- 5 m t l i 6, ReferencesCited in the file of this patent 8. p-(p-Diethylaminoethoxy) phenylstyryl ke- UNITED STATES PATENTS 1501918 1 1 fig ethylaminoethoxy)phenyl 2 -dichlo- Number Name Date rostyryl ketone Oxalate. 10 1,894,865Hartmann et a1. Jan. 17, 1933

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES HAVING THEFOLLOWING FORMULA